Tanshinone-IIA-Based Analogues of Imidazole Alkaloid Act as Potent Inhibitors To Block Breast Cancer Invasion and Metastasis in Vivo

Tanshinone-IIA (Tan-IIA), a primary active component extracted from commonly used Chinese herbal, Salvia miltiorrhiza (Danshen), is considered as a potential inhibitor against tumor cell proliferation. However, the potential application of Tan-IIA is hindered by its poor water solubility and low bioavailability. In this work, an imidazole moiety was linked to the skeleton of Tan-IIA to enhance its antitumor activity. A series of Tan-IIA-based analogues TA01-TA12 were synthesized, and their inhibitory activities against the migration and invasion of MDA-MB-231 cells were investigated. All compounds, particularly TA12, markedly inhibited the proliferation, migration, and invasion of MDA-MB-231cells. TA12 also prominently blocked cancer cell metastasis in blood vessels and surrounding tissues in zebrafish xenograft model. Further studies showed that the mechanisms may involve S-phase arrest pathway, which was probably caused by inducing reactive oxygen species production and activating DNA damage. These results indicated that the Tan-IIA-based analogues of imidazole derivates can act as potent antimetastasis agents.